Substituted 06-benzylguanines and 6(4)-benzyloxypyrimidines

Abstract

The present invention provides 8-substituted O6-benzylguanines of the formula <IMAGE> wherein R1, R2, and R3 are as defined in the specification, and 4(6)-substituted 2-amino-5-nitro-6(4)-benzyloxypyrimidine, and 4(6)-substituted 2-amino-5-nitroso-6(4)-benzyloxypyrimidine derivatives which have been found to be effective AGT inactivators, as well as pharmaceutical compositions comprising such derivatives along with a pharmaceutically acceptable carrier. The present invention further provides a method of enhancing the chemotherapeutic treatment of tumor cells in a mammal with an antineoplastic alkylating agent which causes cytotoxic lesions at the O6-position of guanine, by administering to a mammal an effective amount of one of the aforesaid derivatives, 2,4-diamino-6-benzyloxy-s-triazine, 5-substituted 2,4-diamino-6-benzyloxypyrimidines, or 8-aza-O6-benzylguanine, and administering to the mammal an effective amount of an antineoplastic alkylating agent which causes cytotoxic lesions at the O6-position of guanine.

What is claimed is: 
     
       1. A compound of the formula ##STR8## wherein R 1  is a substituent selected from the group consisting of amino, hydroxy, C 1  -C 4  alkylamino, C 1  -C 4  dialkylamino, and C 1  -C 4  acylamino, R 2  is a substituent selected from the group consisting of hydrogen, C 1  -C 4  alkyl, C 1  -C 4  aminoalkyl, C 1  -C 4  hydroxyalkyl, C 1  -C 4  alkylaminoalkyl, C 1  -C 4  dialkylaminoalkyl, C 1  -C 4  cyanoalkyl, C 1  -C 4  carbamoylalkyl, C 1  -C 4  pivaloylalkyl, C 1  -C 4  carboalkoxyalkyl, ribose, 2'-deoxyribose, the conjugate acid form of a C 1  -C 4  carboxyalkyl, and the carboxylate anion of a C 1  -C 4  carboxyalkyl as the sodium salt, and R 3  is a substituent selected from the group consisting of halo, C 1  -C 4  hydroxyalkyl, thiol, C 1  -C 4  alkylthio, trifluoromethylthio, C 1  -C 4  thioacyl, hydroxy, C 1  -C 4  alkoxy, trifluoromethoxy, oxymethanesulfonyl, oxytrifluoromethanesulfonyl, C 1  -C 4  oxyacyl, amino, C 1  -C 4  aminoalkyl, C 1  -C 4  alkylamino, C 1  -C 4  dialkylamino, trifluoromethylamino, ditrifluoromethylamino, aminomethanesulfonyl, C 1  -C 4  aminoacyl, aminotrifluoromethylcarbonyl, formylamino, nitro, nitroso, C 1  -C 4  alkyldiazo, C 5  -C 6  aryldiazo, trifluoromethyl, C 1  -C 4  haloalkyl, C 1  -C 4  cyanoalkyl, cyano, C 1  -C 4  alkyloxycarbonyl, C 1  -C 4  alkylcarbonyl, phenyl, phenylcarbonyl, formyl, C 1  -C 4  alkoxymethyl, phenoxymethyl, C 2  -C 4  vinyl, C 2  -C 4  ethynyl, and SO n  R' wherein n is 0, 1, 2, or 3 and R' is hydrogen, C 1  -C 4  alkyl, amino, or phenyl. 
     
     
       2. The compound of claim 1, wherein R 1  is amino. 
     
     
       3. The compound of claim 2, wherein R 2  is hydrogen. 
     
     
       4. The compound of claim 3, wherein R 3  is amino. 
     
     
       5. The compound of claim 3, wherein R 3  is hydroxy. 
     
     
       6. The compound of claim 3, wherein R 3  is bromine. 
     
     
       7. The compound of claim 3, wherein R 3  is nitro. 
     
     
       8. The compound of claim 3, wherein R 3  is trifluoromethyl. 
     
     
       9. The compound of claim 2, wherein R 2  is methyl. 
     
     
       10. The compound of claim 9, wherein R 3  is trifluoromethyl. 
     
     
       11. The compound of claim 1, wherein R 1  is hydroxy, C 1  -C 4  alkylamino, C 1  -C 4  dialkylamino, or C 1  -C 4  acylamino. 
     
     
       12. The compound of claim 11, wherein R 2  is hydrogen. 
     
     
       13. The compound of claim 12, wherein R 3  is hydroxy. 
     
     
       14. The compound of claim 13, wherein R 1  is hydroxy, acylamino, methylamino, or dimethylamino. 
     
     
       15. The compound according to claim 1, wherein said compound is selected from the group consisting of 8-amino-O 6  -benzylguanine, 8-hydroxy-O 6  -benzylguanine, 8-bromo-O 6  -benzylguanine, and 8-trifluoromethyl-O 6  -benzylguanine. 
     
     
       16. The compound according to claim 1, wherein said compound is selected from the group consisting of N 2  -acetyl-O 6  -benzyl-8-oxoguanine, and O 6  -benzyl-8-trifluoromethyl-9-methyl-guanine. 
     
     
       17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1. 
     
     
       18. The pharmaceutical composition of claim 17, wherein said pharmaceutically acceptable carrier comprises polyethylene glycol 400. 
     
     
       19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 15. 
     
     
       20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 16. 
     
     
       21. A method of enhancing the chemotherapeutic treatment of tumor cells in a mammal with an antineoplastic alkylating agent that causes cytotoxic lesions at the O 6  -position of guanine, which method comprises: administering to a mammal an effective amount of a compound of claim 1, and   administering to said mammal an effective amount of an antineoplastic alkylating agent which causes cytotoxic lesions at the O 6  -position of guanine.   
     
     
       22. A method of enhancing the chemotherapeutic treatment of tumor cells in a mammal with an antineoplastic alkylating agent that causes cytotoxic lesions at the O 6  -position of guanine, which method comprises: administering to a mammal an effective amount of a compound of claim 15, and   administering to said mammal an effective amount of an antineoplastic alkylating agent which causes cytotoxic lesions at the O 6  -position of guanine.   
     
     
       23. A method of enhancing the chemotherapeutic treatment of tumor cells in a mammal with an antineoplastic alkylating agent that causes cytotoxic lesions at the O 6  -position of guanine, which method comprises: administering to a mammal an effective amount of a compound of claim 16, and   administering to said mammal an effective amount of an antineoplastic alkylating agent which causes cytotoxic lesions at the O 6  -position of guanine.